Implantable medical devices comprising bio-degradable alloys

ABSTRACT

The invention provides medical devices comprising high-strength alloys which degrade over time in the body of a human or animal, at controlled degradation rates, without generating emboli. In one embodiment the alloy is formed into a bone fixation device such as an anchor, screw, plate, support or rod. In another embodiment the alloy is formed into a tissue fastening device such as staple. In yet another embodiment, the alloy is formed into a dental implant or a stent.

The present invention claims priority from U.S. Provisional ApplicationNos. 61/143,378, filed on Jan. 8, 2009, 61/168,554, filed on Apr. 10,2009, and 61/260,363, filed on Nov. 11, 2009, the contents of each ofwhich are expressly incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to biodegradable materials useful formanufacturing implantable medical devices, specifically biodegradablecompositions comprising metal alloys that can provide high strength whenfirst implanted and are gradually eroded and replaced with body tissue.

BACKGROUND OF THE INVENTION

Medical devices meant for temporary or semi-permanent implant are oftenmade from stainless steel. Stainless steel is strong, has a great dealof load bearing capability, is reasonably inert in the body, does notdissolve in bodily fluids, and is durable, lasting for many years, ifnot decades. Long lasting medical implants, however, are not alwaysdesirable. Many devices for fixing bones become problematic once thebone has healed, requiring removal by means of subsequent surgery.Similarly, short term devices such as tissue staples have to be removedafter the tissue has healed, which limits their use internally.

Attempts to generate biodegradable materials have traditionally focusedon polymeric compositions. One example is described in U.S. Pat. No.5,932,459, which is directed to a biodegradable amphiphilic polymer.Another example is described in U.S. Pat. No. 6,368,356, which isdirected to biodegradable polymeric hydrogels for use in medicaldevices. Biodegradable materials for use in bone fixation have beendescribed in U.S. Pat. No. 5,425,769, which is directed to CaSO₄ fibrouscollagen mixtures. And U.S. Pat. No. 7,268,205 describes the use ofbiodegradable polyhydroxyalkanoates in making bone fasteners such asscrews. However, none of the biodegradable polymeric materials developedto date have demonstrated sufficient strength to perform suitably whensubstantial loads must be carried by the material, when the material isrequired to plastically deform during implantation, or when any of theother native characteristic of metal are required from the material. Forexample, the polyhydroxyalkanoate compositions described in U.S. Pat.No. 7,268,205 do not have sufficient strength on their own to bearweight and must be augmented by temporary fixation of bone segments. Inaddition, biodegradable polymeric materials tend to lose strength farmore quickly than they degrade, because the portions of the materialunder stress tend to be more reactive, causing preferential dissolutionand breakdown at load-bearing regions.

Metals, particularly steels, are thus preferred for the construction ofmany medical implants. The performance characteristics of steel closelymatch the mechanical requirements of many load bearing medical devices.Although ordinary steel compounds, unlike stainless steel, will degradein biological fluids, they are not suitable for use in biodegradableimplantable medical devices. This is because ordinary steels do notdegrade in a predictable fashion, as one molecule or group of moleculesat a time, which can be easily disposed of by the body. Rather, becauseof their large-grain structures, ordinary steels tend to break down byfirst degrading at grain boundaries, causing fissures and separations inthe medical device, followed by rapid loss of strength and integrity andparticulation. Particulation of the medical device is extremelydangerous because it allows small pieces of the device to leave the areaof implantation and become lodged in other tissues, where they can causeserious injury including organ failure, heart attack and stroke. The useof ordinary steels in implantable medical devices is also complicated bythe fact that ordinary steels typically contain alloying elements thatare toxic when released in the body.

There remains a need in the field to develop implantable medical devicesthat have desirable characteristics associated with steel but are alsobiodegradable.

SUMMARY OF THE INVENTION

The invention is based, in part, on the discovery that certain metalalloys having, e.g., a fine-grain, substantially austenite structurewill biodegrade over time without forming emboli. The invention is alsobased, in part, on the discovery that certain metal alloys having, e.g.,a substantially martensite structure will biodegrade over time withoutforming emboli. Such alloys are useful for making biodegradable,implantable medical devices.

Accordingly, in one aspect, the invention provides implantable medicaldevices comprising a biodegradable alloy that dissolves gradually fromits exterior surface. In certain embodiments, the rate of dissolutionfrom the exterior surface of the alloy is substantially uniform acrosssmooth portions of the exterior surface (e.g., substantially planar,concave, or convex surfaces). In certain embodiments, the alloy has afine-grain, substantially austenite structure. In related embodiments,the alloy has a substantially austenite structure that does notpreferentially degrade at grain boundaries. In other embodiments, thealloy has a substantially martensite structure.

In certain embodiments, the implantable medical devices comprise analloy that is substantially austenite in structure and has an averagegrain size of about 0.5 microns to about 20 microns. For example, incertain embodiments, the average grain size is about 0.5 microns toabout 5.0 microns, or about 1.0 micron to about 2.0 microns. In certainembodiments, the implantable medical devices comprise an alloy that issubstantially austenite in structure, wherein the surface to volumeratio of individual grains is, on average, greater than 0.1μ⁻¹. Forexample, in certain embodiments, the surface to volume ratio ofindividual grains is, on average, greater than 1.0μ⁻¹.

In certain embodiments, the implantable medical devices comprise analloy that is an iron alloy (e.g., a steel). For example, in certainembodiments, the alloy contains about 55% to about 80% iron. In certainembodiments, the alloy contains at least two non-iron elements, whereineach of said at least two non-iron elements is present in an amount ofat least about 0.5%, and wherein the total amount of said at least twoelements makes up greater than about 20% of the alloy. In certainembodiments, greater than about 5% of the alloy consists of elementsother than iron, chromium, nickel, and carbon. In certain embodiments,the implantable medical devices comprise an alloy that contains lessthan about 0.1% nickel. In certain embodiments, the alloy contains lessthan about 0.1% vanadium. In certain embodiments, the alloy containsless than about 4.0% chromium. In certain embodiments, the alloycontains less than about 6.0% cobalt. In certain embodiments, the alloycontains less than about 0.1% nickel, less than about 0.1% vanadium,less than about 4.0% chromium, and less than about 6.0% cobalt. Incertain embodiments, the alloy contains less than about 0.1% of each ofthe elements in the set consisting of platinum, palladium, iridium,rhodium, rhenium, rubidium, and osmium. In certain embodiments, thealloy contains less than about 0.01% of phosphorus.

In certain embodiments, the implantable medical devices comprise analloy that comprises an austenite promoting component. In certainembodiments, the amount of austenite promoting component in the alloy isgreater than about 10%. In certain embodiments, the austenite promotingcomponent comprises one or more elements selected from the listconsisting of manganese, cobalt, platinum, palladium, iridium, aluminum,carbon, nitrogen, and silicon. In certain embodiments, the austenitepromoting component comprises one or more elements selected from thelist consisting of manganese, cobalt, platinum, palladium, iridium,carbon, and nitrogen, wherein % platinum+% palladium+% iridium+0.5*(%manganese+% cobalt)+30*(% carbon+% nitrogen) is greater than about 12%(e.g., greater than about 14%, about 16%, about 18%, about 19%, or about20%).

In certain embodiments, the implantable medical devices comprise analloy comprising a corrosion resisting component. In certainembodiments, the amount of corrosion resisting component in the alloy isless than about 10% (e.g., about 0.5% to about 10%). In certainembodiments, the corrosion resisting component comprises one or moreelements selected from the list consisting of chromium, molybdenum,tungsten, tantalum, niobium, titanium, zirconium, and hafnium. Incertain embodiments, the corrosion resisting component comprises one ormore elements selected from the list consisting of chromium, molybdenum,tungsten, tantalum, niobium, titanium, zirconium, and hafnium, wherein %chromium+% molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(%titanium+% zirconium+% hafnium) is about 0.5% to about 7% (e.g., about6.0%, about 5.5%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, orabout 3.0%).

In certain embodiments, the alloy comprises an austenite promotingcomponent and a corrosion resisting component. In certain embodiments,the amount of austenite promoting component in the alloy is greater thanabout 10% and the amount of corrosion resisting component in the alloyis about 0.5% to about 10%.

In certain embodiments, the implantable medical device is a high tensilebone anchor (e.g., for the repair of separated bone segments). In otherembodiments, the implantable medical device is a high tensile bone screw(e.g., for fastening fractured bone segments). In other embodiments, theimplantable medical device is a high strength bone immobilization device(e.g., for large bones). In other embodiments, the implantable medicaldevice is a staple for fastening tissue. In other embodiments, theimplantable medical device is a craniomaxillofacial reconstruction plateor fastener. In other embodiments, the implantable medical device is adental implant (e.g., a reconstructive dental implant). In still otherembodiments, the implantable medical device is a stent (e.g., formaintaining the lumen of an opening in an organ of a human or animalbody).

In certain embodiments, the implantable medical device comprises ageometry that maximizes the surface to mass ratio. For example, incertain embodiments, the implantable medical device comprises one ormore openings (e.g., recesses) in the surface of the device or one ormore passageways through the device.

In certain embodiments, the implantable medical device further comprisesa therapeutic agent. In certain embodiments, the therapeutic agent iscoated upon the surface of the device. In other embodiments, thetherapeutic agent is incorporated into the body of the device (e.g.,into the pores of the alloy from which the implantable medical devicewas made, into a recess in the surface of the device, or in a passagewaythrough the device).

In certain embodiments, the implantable medical device further comprisesa biodegradable gel. In certain embodiments, the biodegradable gel iscoated upon the surface of the device. In other embodiments, thebiodegradable gel is incorporated into the body of the device (e.g.,into the pores of the alloy from which the implantable medical devicewas made, into a recess in the surface of the device, or in a passagewaythrough the device). In certain embodiments, the biodegradable gelcomprises a therapeutic agent.

In another aspect, the invention provides a container containing animplantable medical device of the invention. In certain embodiments, thecontainer further comprises an instruction (e.g., for using theimplantable medical device for a medical procedure).

The invention and additional embodiments thereof will be set forth ingreater detail in the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “percentage” when used to refer to the amountof an element in an alloy means a weight-based percentage. “Weightedpercentages” of corrosion resisting and austenite promoting components,however, are calculated in a manner such that the weighted percentagesdo not necessarily correspond to the actual weight-based percentages.

The object of the present invention is to provide medical devices fortemporary implantation in the body of a subject (e.g., a human or animalsubject), wherein the devices are made using a biodegradable alloy. Thebiodegradable alloy is one that is not a stainless steel, but insteadundergoes reactions involving normal body chemistry to biodegrade orbio-absorb over time and be removed by normal body processes. It isanother object of the invention to provide implantable medical devicesmade using a biodegradable alloy that is non-toxic and/or non-allergenicas it is degrading and being processed by the body. It is yet anotherobject of the invention to provide implantable medical devices madeusing a biodegradable alloy that has little or no magneticsusceptibility and does not distort MRI images.

The invention is thus based, in part, on the discovery that certainalloys having, e.g., a fine-grain, substantially austenite structurewill biodegrade over time without forming emboli. These austenite alloysexhibit little or no magnetic susceptibility and can be made non-toxicand/or non-allergenic by controlling the amounts of various metals(e.g., chromium and nickel) incorporated into the alloys. The inventionis also based, in part, on the discovery that certain alloys having,e.g., a substantially martensite structure will biodegrade over timewithout forming emboli. These martensite alloys can also be madenon-toxic and/or non-allergenic by controlling the amounts of variousmetals (e.g., chromium and nickel) incorporated into the alloys. Thealloys may be incorporated into a variety of implantable medical devicesthat are used to heal the body of a subject (e.g., a human or otheranimal), but become unnecessary once the subject is healed. The alloyscan be used, for example, to make biodegradable, implantable medicaldevices that require high strength, such as bone fasteners forweight-bearing bones. The alloys can also be used to make biodegradable,implantable medical devices that require ductility, such as surgicalstaples for tissue fixation.

Accordingly, in one aspect, the invention provides implantable medicaldevices comprising a biodegradable alloy that dissolves from itsexterior surface. As used herein, the term “alloy” means a mixture ofchemical elements comprising two or more metallic elements.Biodegradable alloys suitable for making implantable medical devices ofthe invention can be, for example, iron alloys (e.g., steels). Incertain embodiments, the iron alloys comprise about 55% to about 65%,about 57.5% to about 67.5%, about 60% to about 70%, about 62.5% to about72.5%, about 65% to about 75%, about 67.5% to about 77.5%, about 70% toabout 80%, about 72.5% to about 82.5%, or about 75% to about 85% iron.The iron alloys further comprise one or more non-iron metallic elements.The one or more non-iron metallic elements can include, for example,transition metals, such as manganese, cobalt, nickel, chromium,molybdenum, tungsten, tantalum, niobium, titanium, zirconium, hafnium,platinum, palladium, iridium, rhenium, osmium, rhodium, etc., ornon-transition metals, such as aluminum. In certain embodiments, theiron alloys comprise at least two non-iron metallic elements. The atleast two non-iron elements can be present in an amount of at leastabout 0.5% (e.g., at least about 1.0%, about 1.5%, about 2.0%, about2.5%, about 3.0%, about 4.0%, about 5.0%, or more). In certainembodiments, the iron alloys comprise at least two non-iron metallicelements, wherein each of said at least two non-iron elements is presentin an amount of at least about 0.5%, and wherein the total amount ofsaid at least two elements is at least about 15% (e.g., at least about17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about32.5%, about 35%, about 37.5%, or about 40%). The biodegradable alloyscan also comprise one or more non-metallic elements. Suitablenon-metallic elements include, for example, carbon, nitrogen, andsilicon. In certain embodiments, the iron alloys comprise at least about0.01% (e.g., about 0.01% to about 0.10%, about 0.05% to about 0.15%,about 0.10% to about 0.20%, about 0.15% to about 0.25%, or about 0.20%to about 0.30%) of at least one non-metallic element.

Biodegradable alloys suitable for use in the implantable medical devicesof the invention are designed to degrade from the outside inward, suchthat they maintain their strength for a greater portion of their lifeand do not particulate or embolize. Without intending to be bound bytheory, it is believed that this is accomplished by providing an alloystructure that either has no appreciable reactive grain boundaries,forcing degradation to take place at the surface molecular layer, or byproviding a very fine grain alloy that acts as a homogeneous, grain freematerial. In certain embodiments, the rate of dissolution from anexterior surface of a suitable biodegradable alloy is substantiallyuniform at each point of the exterior surface. As used herein in thiscontext, “substantially uniform” means that the rate of dissolution froma particular point on an exterior surface is +/−10% of the rate ofdissolution at any other point on the same exterior surface. As personsskilled in the art will appreciate, the type of “exterior surface”contemplated in these embodiments is one that is smooth and continuous(i.e., substantially planar, concave, convex, or the like) and does notinclude sharp edges or similar such discontinuities, as those arelocations where the rate of dissolution is likely to be much higher. A“substantially” planar, concave, or convex surface is a surface that isplanar, concave, convex, or the like and does not contain any bumps,ridges, or grooves that rise above or sink below the surface by morethan 0.5 mm.

Steel alloys have iron as their primary constituent. Depending upon acombination of (i) the elements alloyed with the iron and (ii) thehistorical working of the alloy, steels can have different structuralforms, such as ferrite, austenite, martensite, cementite, pearlite, andbainite. In some instances, steels having the same composition can havedifferent structures. For example, martensite steel is a form of hightensile steel that can be derived from austenite steel. By heatingaustenite steel to between 1750° F. and 1950° F., and then rapidlycooling it to below the martensite transition temperature, the facecentered cubic structure of the austenite steel will reorient into abody centered tetragonal martensite structure, and the martensitestructure will freeze into place. Martensite steel does not haveappreciable grain boundaries, and thus provides no primary dissolutionpath to the interior of the steel. The result is a slow dissolution fromthe outside, without the formation of emboli. Metallurgical examinationof martensitic material will show “pre-austenitic grain boundaries,”places where the austenite grain boundaries once existed, but these arenonreactive traces of the former structure.

Accordingly, in certain embodiments, the biodegradable implantablemedical devices of the invention comprise an alloy (e.g., an iron alloy)having a substantially martensite structure. As used herein, the term“substantially martensite structure” means an alloy having at least 90%martensite structure. In certain embodiments, the alloy has at least91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9% or moremartensite structure.

The martensite alloy can have the composition of any alloy describedherein. For example, in certain embodiments, the martensite alloy isformed from an austenite alloy described herein. In certain embodiments,the martensite alloy comprises carbon, chromium, nickel, molybdenum,cobalt, or a combination thereof. For example, in certain embodiments,the martensite alloy comprises (i) carbon, (ii) chromium and/ormolybdenum, and (iii) nickel and/or cobalt. In certain embodiments, themartensite alloy comprises about 0.01% to about 0.15%, about 0.05% toabout 0.20%, about 0.10% to about 0.25%, about 0.01% to about 0.05%,about 0.05% to about 0.10%, about 0.10% to about 0.15%, or about 0.15%to about 0.20% carbon. In certain embodiments, the martensite alloycomprises about 0.1% to about 6.0%, about 1.0% to about 3.0%, about 2.0%to about 4.0%, about 3.0% to about 5.0%, or about 4.0% to about 6.0%chromium. In certain embodiments, the martensite alloy comprises about0.1% to about 6.0%, about 0.5% to about 2.5%, about 1.0% to about 3.0%,about 1.5% to about 3.5%, about 2.0% to about 4.0%, about 2.5% to about4.5%, about 3.0% to about 5.0%, about 3.5% to about 5.5%, or about 4.0%to about 6.0% molybdenum. In certain embodiments, the martensite alloycomprises about 5.0% to about 9%, about 6.0% to about 10%, about 7.0% toabout 11%, about 8.0% to about 12%, about 9.0% to about 13%, about 10%to about 14%, or about 11% to about 15% nickel. In certain embodiments,the martensite alloy comprises about 5.0% to about 10%, about 7.5% toabout 12.5%, about 10% to about 15%, about 12.5% to about 17.5%, orabout 15% to about 20% cobalt.

In certain embodiments, the martensite alloy contains about 2.0% toabout 6.0%, about 3.0% to about 7.0%, about 3.5% to about 7.5%, about4.0% to about 8.0%, about 4.5% to about 8.5%, or about 5.0% to about9.0% of a corrosion resisting component. In certain embodiments, themartensite alloy contains about 2.5%, about 3.0%, about 3.5%, about4.0%, about 4.5%, about 5.0%, about 5.5%, or about 6.0% of a corrosionresisting component. In certain embodiments, the corrosion resistingcomponent is calculated as a sum of the percentages of corrosionresisting elements (e.g., chromium, molybdenum, tungsten, tantalum,niobium, titanium, zirconium, hafnium, etc.) in the alloy. In otherembodiments, the corrosion resisting component is calculated as aweighted sum of the corrosion resisting elements in the alloy. Incertain embodiments, individual elements in the weighted sum areweighted according to their corrosion resisting efficacy, as compared tochromium. In certain embodiments, the weighted % corrosion resistingcomponent is determined according to the formula: % chromium+%molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(% titanium+%zirconium+% hafnium).

In certain embodiments, the martensite alloy contains at least about10%, about 15%, about 18%, about 20%, about 22%, or about 24% of aaustenite promoting component. For example, in certain embodiments, themartensite alloy contains about 10% to about 20%, about 15% to about25%, about 20% to about 30%, about 25% to about 35%, about 30% to about40% of an austenite promoting component. In certain embodiments, themartensite alloy comprises about 22%, about 23%, about 24%, about 25%,about 26%, about 27%, or about 28% of an austenite promoting component.In certain embodiments, the austenite promoting component is calculatedas a sum of the percentages of austenite promoting elements (e.g.,nickel, manganese, cobalt, platinum, palladium, iridium, aluminum,carbon, nitrogen, silicon, etc.) in the alloy. In other embodiments, theaustenite promoting component is calculated as a weighted sum of all theaustenite promoting elements in the alloy. In certain embodiments,individual elements in the weighted sum are weighted according to theiraustenite promoting efficacy, as compared to nickel. In certainembodiments, the weighted % austenite promoting component is calculatedaccording to the formula: % nickel+% platinum+% palladium+%iridium+0.5*(% manganese+% cobalt)+30*(% carbon+% nitrogen).

In certain embodiments, the martensite alloy comprises about 2.0% toabout 4.0%, about 3.0% to about 5.0%, or about 4.0% to about 6.0% of acorrosion resisting component, and about 10% to about 20%, about 15% toabout 25%, about 20% to about 30%, about 25% to about 35%, or about 30%to about 40% of an austenite promoting component. For example, incertain embodiments, the martensite alloy comprises about 3.0% to about5.0% of a corrosion resisting component and about 20% to about 30% of anaustenite promoting component. In certain embodiments, the corrosionresisting and austenite promoting components are calculated as sums ofthe percentages of corrosion resisting and austenite promoting elements,respectively. In other embodiments, the corrosion resisting andaustenite promoting components are calculated as weighted sums of thecorrosion resisting and austenite promoting elements, respectively.

While martensite alloys have the desirable characteristic of lackinggrain boundaries, austenite alloys are particularly useful for medicalimplants because of their low magnetic susceptibility, which can beuseful where the alloy is exposed to a strong magnetic field. It isdesirable for medical implants to have low magnetic susceptibilitybecause they may be used in patients that would have future need ofMagnetic Resonance Imaging (MRI), which utilizes very high magneticfields. A magnetic reactive alloy in a strong magnetic field canexperience heating, causing local tissue stress and damage to tissuesurrounding the implant. Magnetic reactive implants also distort MRIimages, making them unreadable. In addition, austenite alloys canprovide certain mechanical benefits, since they undergo larger plasticdeformations between their elastic limit (yield point) and ultimatefailure, as compared to martensite alloys. For example, whereas amartensite alloy may have a maximum elongation of about 16% to 20%, anaustenite alloy can have a maximum elongation of about 50% to 60%.

Thus, in certain embodiments, the biodegradable implantable medicaldevices of the invention comprise an alloy (e.g., an iron alloy) havinga substantially austenite structure. As used herein, the term“substantially austenite structure” means at least 85% austenitestructure. In certain embodiments, the alloy has at least 88%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9% or moreaustenite structure. In certain embodiments, the austenite alloy hassubstantially no martensite or ferrite structure. As used herein, theterm “substantially no martensite or ferrite structure” means less than5% (e.g., less than 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, or 0.05%)martensite or ferrite structure. In certain embodiments, the austenitealloy is characterized by a maximum elongation of about 40% to about 65%(e.g., about 50% to about 60%).

Austenitic steels have grains with defined boundaries of irregularshape. Since austenite is a face centered cubic structure, the grainstend to be cubic when viewed perpendicular to a major lattice plane. Inaustenite alloys having either very low carbon or very low chromium, itis possible to create a structure with a fine grain size (e.g., about0.5 to about 5.0 microns on a side). A cubic austenite grain of 2.5microns has a total surface area of 37.5 square microns and a volume of15.625 cubic microns, for a surface to volume ratio of 2.4μ⁻¹ and atotal mass of 0.12 micrograms. Because of the extremely small mass ofthe grain, the grain material reacts as quickly as the grain boundarymaterial when placed in a biological environment, allowing the alloy toshed material from the outside. This, in turn, prevents weakening of thematerial bulk along grain boundaries and grain separation from thematerial bulk of the alloy. As the size of grains increase, however, theratio of surface to volume decreases. Each grain becomes bigger, takinglonger to be absorbed, making it more likely that dissolution will takeplace along grain boundaries, penetrating deeper into the alloy'smaterial bulk and thereby reducing the strength of the alloy.

Accordingly, the rate of biodegradation of austenite alloys can bealtered by controlling the grain size and surface to volume ratio of theindividual grains. As the grain size increases, with a commensuratedecrease in the surface-to-volume ratio, biodegradation progressesfaster toward the center of the device, increasing the totalbiodegradation rate. However, too large a grain size can causeseparation of grains and adverse effects.

In certain embodiments, the austenite alloy has an average grain size ofabout 0.5 microns to about 20 microns on each side. For example, incertain embodiments, the average grain size is about 0.5 microns toabout 5.0 microns, about 2.5 microns to about 7.5 microns, about 5.0microns to about 10 microns, about 7.5 microns to about 12.5 microns,about 10 microns to about 15 microns, about 12.5 microns to about 17.5microns, or about 15 microns to about 20 microns on each side. Incertain embodiments, the average grain size is about 0.5 to about 3.0microns, or about 1.0 micron to about 2.0 microns on each side. Incertain embodiments, the austenite alloy has a structure wherein thesurface to volume ratio of individual grains is, on average, greaterthan 0.1μ⁻¹. For example, in certain embodiments, the surface to volumeratio of individual grains is, on average, greater than 0.2μ⁻¹, 0.3μ⁻¹,0.4μ⁻¹, 0.5μ⁻¹, 0.6μ⁻¹, 0.7μ⁻¹, 0.8μ⁻¹, 0.9μ⁻¹, 1.0μ⁻¹, 1.5μ⁻¹, 2.0μ⁻¹,2.5μ⁻¹, 3.0μ⁻¹, 3.5μ⁻¹, 4.0μ⁻¹, 4.5μ⁻¹, 5.0μ⁻¹, 6.0μ⁻¹, 7.0μ⁻¹, 8.0μ⁻¹,9.0μ⁻¹, 10.0μ⁻¹, 11.0μ⁻¹, 12.0μ⁻¹, 13.0μ⁻¹, 14.0μ⁻¹, 15.0μ⁻¹, or more.

Austenite grain sizes of about 0.5 microns to about 20 microns can beachieved by successive cycles of mechanical working to break down thealloy, followed by thermal recrystallization. The mechanical working ofmaterials, whether done at cold temperatures (i.e. room temperature to200° C.) or at elevated temperatures, causes strain-induced disruptionof the crystal structure, by physically forcing the alloy into a newshape. The most common method of mechanical working of metals is byreducing the thickness of a sheet of metal between two high pressurerolls, causing the exiting material to be substantially thinner (e.g.,20%-60% thinner) than the original thickness. Other methods such asdrawing can also be employed. The process of mechanically working metalsbreaks down larger, contiguous lattice units into different structures.More importantly, it stores substantial strain-induced energy intodistorted lattice members, by straining lattice structure distances tohigher energy arrangements. Subsequent low-temperaturerecrystallization, which takes place at about 0.35 to about 0.55 timesthe absolute melting temperature of the alloy, allows the latticestructure to undergo rearrangements to a lower energy condition, withoutchanges to overall macro dimensions. To accommodate latticerearrangement without gross changes in dimensions, the size ofindividual lattice sub-units, or grains, is reduced, releasingsubstantial strain energy by breaking the lattice into smallersub-units, and producing a finer grain structure. The process ofmechanical working followed by recrystallization can be repeatedserially, producing finer and finer grains.

In certain embodiments, the austenite alloy comprises carbon. Forexample, in certain embodiments, the alloy comprises about 0.01% toabout 0.10%, about 0.02% to about 0.12%, about 0.05% to about 0.15%,about 0.07% to about 0.17%, about 0.10% to about 0.20%, about 0.12% toabout 0.22%, or about 0.15% to about 0.25% carbon. In certainembodiments, the austenite alloy comprises one or more (e.g., two ormore) elements selected from the list consisting of nickel, cobalt,aluminum, and manganese. In certain embodiments, the alloy comprisesabout 2.0% to about 6.0%, about 3.0% to about 7.0%, about 4.0% to about8.0%, or about 5.0% to about 9.0% nickel. In other embodiments, thealloy comprises substantially no nickel. In certain embodiments, thealloy comprises about 10% to about 20%, about 15% to about 20%, about15% to about 25%, about 18% to about 23%, about 20% to about 25%, orabout 20% to about 30% cobalt. In certain embodiments, the alloycomprises less than about 5.0% (e.g., less than about 4.5%, about 4.0%,about 3.5%, about 3.0%, or about 2.5%) manganese. In certainembodiments, the alloy comprises about 0.5% to about 1.5%, about 1.0% toabout 2.0%, or about 1.5% to about 2.5% manganese. In other embodiments,the alloy comprises about 1.0% to about 8.0%, about 6.0% to about 10%,about 8.0% to about 12%, or about 10% to about 14% manganese. In certainembodiments, the austenite alloy comprises one or more (e.g., two ormore) elements selected from the list consisting of chromium,molybdenum, and tantalum. In certain embodiments, the alloy comprisesabout 0.5% to about 1.5%, about 1.0% to about 2.0%, about 1.5% to about2.5%, or about 2.0% to about 3.0% chromium. In other embodiments, thealloy comprises substantially no chromium. In certain embodiments, thealloy comprises about 0.5% to about 1.5%, about 1.0% to about 2.0%,about 1.5% to about 2.5%, or about 2.0% to about 3.0% molybdenum. Incertain embodiments, the alloy comprises about 1.0% to about 3.0%, about2.0% to about 4.0%, about 3.0% to about 5.0%, or about 4.0% to about6.0% tantalum. In certain embodiments, the austenite alloy comprises (i)carbon, (ii) at least two elements selected from the list consisting ofnickel, cobalt, aluminum, and manganese, and (iii) at least two elementsselected from the list consisting of chromium, molybdenum, and tantalum.

Aside from the pattern of dissolution, the rate of dissolution and therelease of potentially toxic elements need to be controlled in alloysused to make implantable medical devices of the invention. Theparticular elements used to make up an alloy help determine the physicaland chemical properties of the resulting alloy. For example, addingsmall amounts of carbon to iron changes the structure of the iron,creating steel that is greatly increased in hardness and strength, whilechanging the plasticity relative to iron. Similarly, stainless steelsare fabricated by adding elements to the iron that decrease corrosion(i.e., corrosion resisting components), such as chromium and molybdenum.A stainless steel that resists corrosion in a biological system cancontain, for example, 18% chromium and 1% molybdenum. Titanium, niobium,tantalum, vanadium, tungsten, zirconium, and hafnium likewise provide aprotective effect that slows down the rate of degradation of steel in abiologic system.

A stainless steel that does not break down in the intended biologicalsystem is typically not suitable for use in a biodegradable implant.Thus, alloys having large quantities of corrosion resisting elements,such as chromium, molybdenum, titanium, and tantalum, usually cannot beused to make biodegradable implantable medical devices of the invention.However, small quantities of such corrosion resisting elements areuseful for controlling the biodegradation rate of suitable alloys.Accordingly, in certain embodiments, an alloy useful for making abiodegradable implantable medical device of the invention (e.g., anaustenite alloy) contains at least about 0.5%, about 1.0%, about 1.5%,about 2.0%, about 2.5%, about 3.0%, or about 3.5%, but less than about15%, about 12%, about 11%, about 10%, about 9.0%, about 8.0% or about7.0% of a corrosion resisting component. For example, in certainembodiments, the alloy contains about 1.0% to about 7.0%, about 2.0% toabout 8.0%, or about 3.0% to about 9.0% of a corrosion resistingcomponent. In certain embodiments, the alloy (e.g., austenite alloy)contains about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%,about 5.5%, about 6.0%, about 6.5%, or about 7.0% of a corrosionresisting component. In certain embodiments, the corrosion resistingcomponent is calculated as a sum of the percentages of corrosionresisting elements (e.g., chromium, molybdenum, tungsten, tantalum,niobium, titanium, zirconium, hafnium, etc.) in the alloy. In otherembodiments, the corrosion resisting component is a weighted sum of allthe corrosion resisting elements in the alloy. For example, in certainembodiments, individual elements in the weighted sum are weightedaccording to their corrosion resisting efficacy, as compared tochromium. In certain embodiments, the weighted % corrosion resistingcomponent is determined according to the formula: % chromium+%molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(% titanium+%zirconium+% hafnium).

Corrosion resisting elements, such as chromium and molybdenum, areferrite promoting and tend to cause steel to form a ferritic structure.To overcome such ferrite promotion and achieve an austenite structure,austenite promoting elements can be added to the alloy. Austenitepromoting elements include, for example, nickel, manganese, cobalt,platinum, palladium, iridium, aluminum, carbon, nitrogen, and silicon.Accordingly, in certain embodiments, an alloy (e.g., an austenite alloy)useful for making an implantable medical device of the inventioncontains an austenite promoting component. In certain embodiments, thealloy contains about 10% to about 20%, about 15% to about 25%, about 20%to about 30%, about 25% to about 35%, or about 30% to about 40% of anaustenite promoting component. In certain embodiments, the alloycontains at least about 10%, about 12%, about 14%, about 16%, about 18%,about 20%, about 22%, about 24%, about 26%, about 28%, or about 30% ofan austenite promoting component. In certain embodiments, the austenitepromoting component is calculated as a sum of the percentages ofaustenite promoting elements (e.g., nickel, cobalt, manganese, platinum,palladium, iridium, aluminum, carbon, nitrogen, silicon, etc.) in thealloy. In other embodiments, the austenite promoting component is aweighted sum of the austenite promoting elements in the alloy. Incertain embodiments, individual elements in the weighted sum areweighted according to their austenite promoting efficacy, as compared tonickel. In certain embodiments, the weighted % austenite promotingcomponent is calculated according to the formula: % nickel+% platinum+%palladium+% iridium+0.5*(% manganese+% cobalt)+30*(% carbon+% nitrogen).In certain embodiments, the alloy contains a weighted % austenitepromoting component of about 15% to about 25% (e.g., about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, or about 25%). In certain embodiments, the alloy contains anunweighted % austenite promoting component of about 25% to about 35%(e.g., about 28%, about 29%, about 30%, about 31%, about 32%, about 33%,about 34%, or about 35%).

In certain embodiments, an alloy (e.g., an austenite alloy) useful formaking an implantable medical device of the invention contains less thanabout 5.0% (e.g., about 0.1% to about 2.5%, about 0.5% to about 3.0%,about 1.0% to about 3.5%, about 1.5% to about 4.0%, or about 2.0% toabout 4.5%) of platinum, iridium, and osmium, either individually or intotal. In certain embodiments, the alloy contains substantially noplatinum, palladium, or iridium. As used herein, “substantially no”platinum, palladium, or iridium means that the alloy contains less than0.1% of platinum, palladium, or iridium. In certain embodiments, thealloy contains substantially none platinum, palladium, and iridium. Incertain embodiments, the alloys contain less than about 0.05%, or about0.01% of each of platinum, palladium, or iridium. In certainembodiments, the alloys contain less than about 0.05%, or less thanabout 0.01%, of each of platinum, palladium, and iridium. In otherembodiments, the total amount of platinum, iridium, and osmium in thealloy is about 5.0% or greater, and the alloy further comprises at leastone additional metal element other than iron, manganese, platinum,iridium, and osmium (e.g., at least about 0.5% or more of said at leastone additional metal element). In certain embodiments, the at least oneaddition metal element is a corrosion resisting element (e.g., chromium,molybdenum, tungsten, titanium, tantalum, niobium, zirconium, orhafnium) or a austenite promoting element selected from the groupconsisting of nickel, cobalt, and aluminum.

Biodegradable alloys implanted in a human or animal body need to berelatively non-toxic because all of the elements in the alloys willeventually be dissolved into body fluids. Nickel is often used tostabilize an austenitic crystal structure. However, many people havenickel allergies and cannot tolerate nickel ions in their systems.Having nickel as part of a biodegradable alloy guarantees that all ofthe nickel in the alloy will eventually be absorbed by the host's body,which can cause complications in a nickel sensitive individual.Likewise, chromium, cobalt, and vanadium have some toxicity in the humanbody, and should be minimized in a biodegradable alloy. Accordingly, incertain embodiments, an alloy useful for making a biodegradableimplantable medical device of the invention (e.g., an austenite alloy)contains less than about 9.0%, about 8.0%, about 7.0%, about 6.0%, about5.0%, about 4.0%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about1.0%, or about 0.5% of each of nickel, vanadium, chromium, and cobalt.In certain embodiments, the alloy contains substantially no nickel. Asused here, the phrase “substantially no nickel” means that the alloycontains 0.1% or less nickel. In certain embodiments, the alloy containsless than about 0.05%, less than about 0.02%, or less than about 0.01%nickel. In certain embodiments, the alloy contains substantially novanadium. As used here, the phrase “substantially no vanadium” meansthat the alloy contains 0.1% or less vanadium. In certain embodiments,the alloy contains less than about 0.05%, less than about 0.02%, or lessthan about 0.01% vanadium. In certain embodiments, the alloy containsless than about 4.0% chromium (e.g., less than about 3.0%, about 2.0%,or about 1.5%). In certain embodiments, the alloy contains substantiallyno chromium. As used here, the phrase “substantially no” chromium meansthat the alloy contains 0.1% or less chromium. In certain embodiments,the alloy contains less than about 0.05%, less than about 0.02%, or lessthan about 0.01% chromium. In certain embodiments, the alloy containsless than about 6.0% (e.g., less than about 5.0%, about 4.0%, about3.0%, about 2.0%, or about 1.0%) cobalt.

To remove or minimize toxic elements from the alloys used to created thebiodegradable implantable medical devices of the invention, the toxicelements can be replaced with non-toxic counterparts. For example, sincenickel is used as an austenite promoting element, it can be replacedwith other austenite promoting elements, such as manganese, cobalt,platinum, palladium, iridium, aluminum, carbon, nitrogen, and silicon.Similarly, since chromium is used as a corrosion resisting element, itcan be replaced with other corrosion resisting elements, such asmolybdenum, tungsten, titanium, tantalum, niobium, zirconium, andhafnium. However, not all alloy substitutions are equivalent. For acorrosion resisting effect, molybdenum is as effective as chromium,while niobium and tantalum are only half as effective as chromium, andtitanium is twice as effective as chromium. For austenite promotingeffect, manganese and cobalt are only half as effective as nickel, whilecarbon is 30 times more effective than nickel, and nitrogen is 25-30times more effective than nickel. Accordingly, in certain embodiments, abiodegradable alloy is rendered non-allergenic or less allergenic byreplacing one part of nickel with two parts manganese, one part ofmanganese and one part of cobalt, or two parts of cobalt. In otherembodiments, a biodegradable alloy is rendered non-toxic or less toxicby replacing one part of chromium with one part of molybdenum, half apart of titanium, or two parts of tantalum or niobium. In certainembodiments, the total percentage of nickel, cobalt and manganese isfrom about 10% to about 20%, about 15% to about 25%, or about 20% toabout 30%, about 25% to about 35%, or about 30% to about 40%, whereinthe percentage of nickel is less than about 9.0%, about 8.0%, about7.0%, about 6.0%, about 5.0%, about 4.0%, or about 3.0%. In otherembodiments, the total percentage of chromium and molybdenum is fromabout 1.0% to about 7.0%, about 2.0% to about 8.0%, about 3.0% to about9.0%, or about 4.0% to about 10%, wherein the amount of chromium is lessthan about 2.0%, about 1.5%, about 1.0%, or about 0.5%.

Additional elements that can be included in alloys useful for makingbiodegradable, implantable medical devices of the invention includerhodium, rhenium, and osmium. In certain embodiments, the amount ofrhodium, rhenium, or osmium in the alloy is less that about 5.0% (e.g.,about 0.1% to about 2.5%, about 0.5% to about 3.0%, about 1.0% to about3.5%, about 1.5% to about 4.0%, or about 2.0% to about 4.5%). In certainembodiments, there is substantially no rhodium, rhenium, or osmium inthe alloy. As used herein, “substantially no” rhodium, rhenium, orosmium means that the alloy contains less than about 0.1% of rhodium,rhenium, or osmium. In certain embodiments, there is substantially nonerhodium, rhenium, and osmium in the alloy. In certain embodiments, thealloy contains less than about 0.05%, or less than about 0.01%, ofrhodium, rhenium, or osmium. In certain embodiments, the alloy containsless than about 0.05%, or less than about 0.01%, of each of rhodium,rhenium, and osmium.

In certain embodiments, when one or more elements selected from thegroup consisting of platinum, palladium, iridium, rhodium, rhenium, andosmium is present in an alloy useful for making biodegradable,implantable medical devices of the invention, the amount of manganese inthe alloy is less than about 5.0% (e.g., less than about 4.5%, about4.0%, about 3.5%, about 3.0%, or about 2.5%). In other embodiments, whenone or more elements selected from the group consisting of platinum,palladium, iridium, rhenium, rubidium, and osmium is present in thealloy and the amount of manganese in the alloy is about 5.0% or greater(e.g., about 5.0% to about 30%), then the alloy further comprises atleast one additional metal element. In certain embodiments, the at leastone addition metal element is a corrosion resisting element (e.g.,chromium, molybdenum, tungsten, titanium, tantalum, niobium, zirconium,or hafnium) or a austenite promoting element selected from the groupconsisting of nickel, cobalt, and aluminum.

In certain embodiments, alloys useful for making biodegradable,implantable medical devices of the invention contain substantially norubidium or phosphorus. As used herein, “substantially no” rubidium orphosphorus means less than 0.1% of rubidium of phosphorus. In certainembodiments, the alloys contain substantially none rubidium andphosphorus. In certain embodiments, the alloys contain less than about0.05%, or less than about 0.01%, of rubidium or phosphorus. In certainembodiments, the alloys contain less than about 0.05%, or less thanabout 0.01%, of each of rubidium and phosphorus.

In certain embodiments, the present invention provides biodegradableimplantable medical devices comprising a range of biodegradable alloys(e.g., austenitic alloys) that are acceptably non-allergenic, non-toxic,have little or no magnetic susceptibility, and provide a useful range ofdegradation rates. The following are exemplary boundaries definingalloys useful in the biodegradable implantable medical devices of thepresent invention:

-   -   substantially no nickel;    -   substantially no vanadium;    -   less than about 6.0% chromium;    -   less than about 10% cobalt;    -   a corrosion resisting component of less than about 10% (e.g.,        about 0.5% to about 10%); and    -   an austenite promoting component of at least about 10% (e.g.,        about 10% to about 40%).

In certain embodiments, the alloys contain about 55% to about 80% iron.For example, in certain embodiments, the alloys contain about 55% toabout 65%, about 60% to about 70%, about 65% to about 75%, about 70% toabout 80% iron. In certain embodiments, the amount of chromium is lessthan about 4.0% and the amount of cobalt is less than about 6.0%. Incertain embodiments, the amount of chromium is less than about 2.0% andthe amount of cobalt is less than about 4.0%. In certain embodiments,the corrosion resisting component is less than about 8.0% (e.g., about0.5% to about 8.0%) and the austenite promoting component is greaterthan about 12%. In certain embodiments, the corrosion resistingcomponent is less than less than about 7.0% (e.g., about 0.5% to about7.0%) and the austenite promoting component is greater than about 14%.In certain embodiments, the corrosion resisting component is less thanabout 6.0% (e.g., about 0.5% to about 6.0%) and the austenite promotingcomponent is greater than about 16%. In certain embodiments, thecorrosion resisting and austenite promoting components are calculated assums of the percentages of corrosion resisting and austenite promotingelements, respectively. In other embodiments, the corrosion resistingand austenite promoting components are calculated as weighted sums ofthe corrosion resisting and austenite promoting elements, respectively.In certain embodiments, the weighted % corrosion resisting component isdetermined according to the formula: % chromium+% molybdenum+%tungsten+0.5*(% tantalum+% niobium)+2*(% titanium+% zirconium+%hafnium). In certain embodiments, the weighted % austenite promotingcomponent is calculated according to the formula: % nickel+% platinum+%palladium+% iridium+0.5*(% manganese+% cobalt)+30*(% carbon+% nitrogen).In certain embodiments, the alloys contain less than about 5.0%manganese (e.g., less than about 4.5%, about 4.0%, about 3.5%, about3.0%, or about 2.5%). In certain embodiments, the alloys contain one ormore elements selected from the group consisting of platinum, palladium,iridium, rhodium, rhenium, and osmium. In certain embodiments, thealloys contain about 0.5% to about 5.0% of one or more elements selectedfrom the group consisting of platinum, palladium, iridium, rhodium,rhenium, and osmium. In certain embodiments, the alloys containsubstantially none of the elements selected from the group consisting ofplatinum, palladium, iridium, rhodium, rhenium, and osmium. In certainembodiments, the alloys contain substantially none of the elementsselected from the group consisting of rubidium and phosphorus.

The degradation of an entire implant is a function of the mass of theimplant as compared to its surface area. Implants come in many differentsizes and shapes. A typical coronary stent, for example, weighs 0.0186grams and has a surface area of 0.1584 square-inches. At a degradationrate of 1 mg/square-inch/day, a coronary stent would loose 50% of itsmass in 30 days. In comparison, a 12 mm long cannulated bone screwweighs 0.5235 g and has a surface area of 0.6565 square-inches. At thesame degradation rate of 1 mg/square-inch/day, the cannulated screw willloose half of its mass in 363 days. Thus, as persons skilled in the artwill readily appreciate, it is desirable to have biodegradable alloysthat have a range of degradation rates to accommodate the variety ofimplants used in the body of a subject.

In addition, the biodegradation rate of the implantable medical devicesof the present invention are significantly influenced by the transportcharacteristics of the surrounding tissue. For example, thebiodegradation rate of an implant placed into bone, where transport tothe rest of the body is limited by the lack of fluid flow, would beslower than a vascular stent device that is exposed to flowing blood.Similarly, a biodegradable device embedded in tissue would have slowerdegradation rate than a device exposed to flowing blood, albeit a fasterdegradation rate than if the device was embedded in bone. Moreover,different ends of a medical device could experience different rates ofdegradation if, for example, one end is located in bone and the otherend is located in tissue or blood. Modulation of biodegradation ratesbased on the location of the device and ultimate device requirements isthus desirable.

In order to control the dissolution rate of a medical device independentof the geometric shape changes that occur as the device degrades,several techniques have been developed. The first method to alter thedissolution profile of a metallic device is to alter the geometry of thedevice such that large changes in surface area are neutralized. Forexample, the surface to mass ratio can be increased or maximized. Asubstantially cylindrical device, which would lose surface area linearlywith the loss of diameter as the device degrades, could have aconcentric hole drilled through the center of the device. The resultingcavity would cause a compensating increase in surface area as alloy wasdissolved from the luminal surface of the device. As a result, thechange in surface area as the device degrades over time—and thus thechange in rate of degradation—would be minimize or eliminated. A similarstrategy of creating a luminal space (e.g., a luminal space that has ashape similar to the outer surface of the device) could be implementedwith essentially any type of medical device.

Because biodegradation rates are partially a function of exposure tobodily fluid flow, biodegradation rates can be modified by coating(e.g., all or part of) the biodegradable implantable medical device witha substance that protects the alloy surface. For example, biodegradablehydrogels, such as disclosed in U.S. Pat. No. 6,368,356, could be usedto retard exposure of any parts of a device exposed to mobile bodilyfluids, thereby retard dissolution and transport of metal ions away fromthe device. Alternatively, medical devices can be constructed with twoor more different alloys described herein, wherein parts of the devicethat are exposed to mobile bodily fluids are made from more corrosionresistant alloys (i.e., alloys comprising higher amounts of a corrosionresisting component), while parts of the device imbedded in bone ortissue are made from less corrosion resistant alloys. In certainembodiments, the different parts of the device can be made entirely fromdifferent alloys. In other embodiments, parts of the device exposed tomobile bodily fluids can have a thin layer or coating of an alloy thatis more corrosion resistant than the alloy used to make the bulk of thedevice.

It is frequently desirable to incorporate bioactive agents (e.g., drugs)on implantable medical devices. For example, U.S. Pat. No. 6,649,631claims a drug for the promotion of bone growth which can be used withorthopedic implants. Bioactive agents may be incorporated directly onthe surface of an implantable medical device of the invention. Forexample, the agents can be mixed with a polymeric coating, such as ahydrogel of U.S. Pat. No. 6,368,356, and the polymeric coating can beapplied to the surface of the device. Alternatively, the bioactiveagents can be loaded into cavities or pores in the medical devices whichact as depots such that the agents are slowly released over time. Thepores can be on the surface of the medical devices, allowing forrelatively quick release of the drugs, or part of the gross structure ofthe alloy used to make the medical device, such that bioactive agentsare released gradually during most or all of the useful life of thedevice. The bioactive agents can be, e.g., peptides, nucleic acids,hormones, chemical drugs, or other biological agents, useful forenhancing the healing process.

As persons skilled in the art will readily recognize, there are a widearray of implantable medical devices that can be made using the alloysdisclosed herein. In certain embodiments, the implantable medical deviceis a high tensile bone anchor (e.g., for the repair of separated bonesegments). In other embodiments, the implantable medical device is ahigh tensile bone screw (e.g., for fastening fractured bone segments).In other embodiments, the implantable medical device is a high strengthbone immobilization device (e.g., for large bones). In otherembodiments, the implantable medical device is a staple for fasteningtissue. In other embodiments, the implantable medical device is acraniomaxillofacial reconstruction plate or fastener. In otherembodiments, the implantable medical device is a dental implant (e.g., areconstructive dental implant). In still other embodiments, theimplantable medical device is a stent (e.g., for maintaining the lumenof an opening in an organ of an animal body).

Powdered metal technologies are well known to the medical devicecommunity. Bone fasteners having complex shapes are fabricated by highpressure molding of a powdered metal in a carrier, followed by hightemperature sintering to bind the metal particles together and removethe residual carrier. Powdered metal devices are typically fabricatedfrom nonreactive metals such as 316LS stainless steel. The porosity ofthe finished device is partially a function of the metal particle sizeused to fabricate the part. Because the metal particles are much largerand structurally independent of the grains in the metal's crystalstructure, metal particles (and devices made from such particles) can bemade from alloys of any grain size. Thus, biodegradable implantablemedical devices of the invention can be fabricated from powders madefrom any of the alloys described herein. The porosity resulting from thepowdered-metal manufacturing technique, can be exploited, for example,by filling the pores of the medical devices with biodegradable polymers.The polymers can be used to retard the biodegradation rates of all orpart of the implanted device, and/or mixed with bioactive agents (e.g.,drugs) that enhance the healing of the tissue surrounding the device. Ifthe porosity of the powdered metal device is filled with a drug, thedrug will be delivered as it becomes exposed by the degradation of thedevice, thereby providing drug to the tissue site as long as the deviceremains present and biodegrading.

In certain embodiments, the implantable medical device is designed forimplantation into a human. In other embodiments, the implantable medicaldevice is designed for implantation into a pet (e.g., a dog, a cat). Inother embodiments, the implantable medical device is designed forimplantation into a farm animal (e.g., a cow, a horse, a sheep, a pig,etc.). In still other embodiments, the implantable medical device isdesigned for implantation into a zoo animal.

In another aspect, the invention provides a container containing animplantable medical device of the invention. In certain embodiments, thecontainer is a packaging container, such as a box (e.g., a box forstoring, selling, or shipping the device). In certain embodiments, thecontainer further comprises an instruction (e.g., for using theimplantable medical device for a medical procedure).

The following examples are intended to illustrate, but not to limit, theinvention in any manner, shape, or form, either explicitly orimplicitly. While the specific alloys described exemplify alloys thatcould be used in implantable medical devices of the invention, personsskilled in the art will be able to readily identify other suitablealloys in light of the present specification.

EXAMPLES Example 1

A “condition A” martensitic steel composed of 0.23% carbon, 3.1%chromium, 11.1% nickel, 1.2% molybdenum, 13.4% cobalt and 70.97% ironwas obtained from Carpenter Steel. The steel was heat treated it in areducing atmosphere at 1250° C. for 12 hours, followed by slow cooling.Afterwards, the material was tested for Rockwell Hardness, yielding ahardness range of 31-32 on the Rockwell C scale. The steel was then cutinto pieces of various dimensions:

-   -   (1) 0.514″ width by 0.0315″ length by 0.020″ thick, having a        surface to volume ratio of about 167.4 and weighing about 48.2        mg;    -   (2) 0.514″ width by 0.0315″ length by 0.050″ thick, having a        surface area to volume of about 107.4 and weighing about 119.8        mg; and    -   (3) 0.514″ width by 0.0315″ width by 0.500″ thick, having a        surface to volume ratio of about 71.4 and weighing about 1207.7        mg.

Each piece of steel was immersed in 10 ml of human blood at 37° C. undergentle rocking. At one week intervals the pieces were retrieved, weighedand tested for Rockwell hardness. The test pieces demonstrated adegradation rate matching the linear formula L=0.74·S, where L is theloss in milligrams per day and S is the total surface area. No loss inhardness of the material was apparent up the point that the materialthickness became too thin to measure, demonstrating that material losswas from the exterior surfaces with no degradation of the interiormaterial.

Example 2

An austenite steel comprising 0.1% carbon, 0.45% manganese, and 99.45%iron and having no contaminating elements greater than 0.05% wasobtained from a commercial source. The alloy was etched and tested forgrain size and Rockwell hardness. The alloy was then cut into severalpieces having dimensions of about 0.5″ wide by about 0.5″ long by about0.005″ thick.

The pieces of austenite steel were tested for hardness and then immersedin 10 CC of blood at 37° C. with gentile agitation. The pieces wereremoved at weekly intervals, weighed, tested for hardness andre-immersed in fresh blood for the next period. The resultingdissolution into the blood samples followed the linear formula L=1.05·S,where L is the loss in milligrams per day and S is the total surfacearea. No loss of hardness was apparent up to the point that materialthickness became too thin to make a hardness measurement.

In both of the above experiments, the dissolution rate was largely afunction of the total surface area which, due to the shape of the testpieces, changed very little throughout the experiment. In device shapesmore consistent with practical implants, the surface of the device willbe reduced in surface area as the device is dissolved and replaced withbody tissues. The reduction in surface area will reduce the rate ofmetal loss, causing the ultimate loss curve to be a geometric functionof the remaining device surface area. Thus, as persons skilled in theart will readily appreciate, rate of loss of an implanted device willlargely be a function of the geometry of the device.

Example 3

Some examples of austenite alloys suitable for use in implantablemedical devices of the invention are as follows:

Alloy 1: Carbon 0.1% Nickel 6.0% Cobalt 20.0%  Manganese 1.0% Chromium2.0% Molydbenum 2.0% Iron 68.9%  Alloy 2: Carbon 0.1% Nickel 6.0% Cobalt20.0%  Manganese 8.0% Chromium 2.0% Tantalum 4.0% Iron 59.9%  Alloy 3:Carbon 0.1% Nickel 0.0% Cobalt 20.0%  Manganese 10.0%  Molydbenum 2.0%Tantalum 4.0% Iron 63.9%  Alloy 4: Carbon 0.08%  Nickel 0.0% Manganese28.0%  Titanium 3.0% Iron 68.92% 

As persons skilled in the art will readily appreciate, the foregoingalloys may contain some impurities that cause the actual percentages ofeach element in the alloy to be slightly lower than shown above.

Example 4

Thin flat samples approximately 0.5 inches square and 0.05 inches thickwere prepared from a martensitic steel composed of 0.23% carbon, 3.1%chromium, 11.1% nickel, 1.2% molybdenum, 13.4% cobalt, and the balanceiron. The flat shape was chosen so that there would be very littlechange in surface area as the samples degraded. The samples were cleanedand weighed. All samples were then immersed in buffered saline at 37° C.with slow orbital shaking. Half of the samples were allowed to oxidizein air, forming protective chromium oxides on the surface prior toimmersion, and the other half were immersed immediately after cleaning.Samples were removed at intervals between one week and 136 days driedand weighed. Samples that were immersed immediately after cleaningexperienced a constant weight loss of 1.1 mg per square inch per dayover the study period. Samples that were oxidized prior to immersionexperienced a weight loss of 0.6 mg per day per square inch of surface.The protective effect of chromium oxide reduced the degradation rate byapproximately 50%.

Example 5

An austenitic alloy composed of 0.08% carbon, 18% manganese, 5% cobalt,0.5% molybdenum, 1% tantalum, and 2% chromium was melted, upset forgedand hot rolled to approximately 0.094 inches thick. The alloy had ahardness of approximately Rockwell C 45. Samples were immersed inbuffered saline at 37° C. with slow orbital shaking The samples wereperiodically rinsed, dried and weighed for a three month period. Thesamples experienced a constant weight loss of 1.07 mg per square inchper day.

Example 6

An austenitic alloy composed of 0.08% carbon, 18% manganese, 5% cobalt,0.5% molybdenum, 1% tantalum, and 2% chromium was melted, upset forgedand hot rolled to approximately 0.094 inches thick. The alloy wasfurther annealed at 1800° F., after which the alloy had a hardness ofapproximately Rockwell C 25. Samples were immersed in buffered saline at37° C. with slow orbital shaking The samples were periodically rinsed,dried and weighed for a three month period. The samples experienced aconstant weight loss of 0.92 mg per square inch per day.

Example 7

An austenitic alloy composed of 0.08% carbon, 18% manganese, 5% cobalt,0.5% molybdenum, 1% niobium, and 2% chromium was melted, upset forgedand hot rolled to approximately 0.094 inches thick. The alloy had ahardness of approximately Rockwell C 45. Samples were immersed inbuffered saline at 37° C. with slow orbital shaking The samples wereperiodically rinsed, dried and weighed for a three month period. Thesamples experienced a constant weight loss of 1.08 mg per square inchper day.

Example 8

An austenitic alloy composed of 0.08% carbon, 18% manganese, 5% cobalt,0.5% molybdenum, 1% niobium, and 2% chromium was melted, upset forgedand hot rolled to approximately 0.094 inches thick. The alloy wasfurther annealed at 1800° F., after which the alloy had a hardness ofapproximately Rockwell C 25. Samples were immersed in buffered saline at37° C. with slow orbital shaking The samples were periodically rinsed,dried and weighed for a three month period. The samples experienced aconstant weight loss of 0.98 mg per square inch per day.

Although the invention has been described with reference to thepresently preferred embodiments, it should be understood that variouschanges and modifications, as would be obvious to one skilled in theart, can be made without departing from the spirit of the invention.Accordingly, the invention is limited only by the following claims.

1. An implantable medical device comprising a biodegradable alloy,wherein the alloy is substantially austenite in structure, wherein thealloy has an average grain size in the range of about 0.5 microns toabout 20 microns and a reactive surface to volume ratio for individualgrains of, on average, greater than 0.1μ⁻¹, wherein the average grainsize is stable at minimum recrystallization temperature of 0.55 timesthe absolute melting temperature of the alloy and wherein the rate ofdissolution from the exterior surface of the biodegradable alloy issubstantially uniform at each point of the exterior surface.
 2. Theimplantable medical device of claim 1, wherein the average grain size isabout 0.5 microns to about 5.0 microns.
 3. The implantable medicaldevice of claim 1, wherein the average grain size is about 1.0 micron toabout 2.0 microns.
 4. The implantable medical device of claim 1, whereinthe implantable device is a bone screw, bone anchor, tissue staple,craniomaxillofacial reconstruction plate, fastener, reconstructivedental implant, or stent.
 5. The implantable medical device of claim 1,wherein the alloy comprises an austenite promoting component and acorrosion resisting component, and wherein the total amount of theaustenite promoting component in the alloy is greater than about 10% andthe total amount of the corrosion resisting component is about 0.5% toabout 10%.
 6. The implantable medical device of claim 1, wherein thealloy contains less than about 0.1% nickel and less than about 0.1%vanadium.
 7. The implantable medical device of claim 1, wherein thealloy contains less than about 4% chromium.
 8. The implantable medicaldevice of claim 1, wherein the alloy contains less than about 6% cobalt.9. The implantable medical device of claim 1, wherein the alloy containsless than about 0.1% nickel, less than about 0.1% vanadium, less thanabout 4% chromium, and less than about 6% of cobalt.
 10. The implantablemedical device of claim 1, wherein the alloy comprises an austenitepromoting component comprising manganese, cobalt, platinum, palladium,iridium, aluminum, carbon, nitrogen, silicon, or any combinationthereof, and wherein % platinum+% palladium+% iridium+0.5*(% manganese+%cobalt)+30*(% carbon+% nitrogen) is greater than about 12%.
 11. Theimplantable medical device of claim 1, wherein the alloy comprises acorrosion resisting component comprising chromium, molybdenum, tungsten,tantalum, niobium, titanium, zirconium, hafnium, or any combinationthereof, and wherein % chromium+% molybdenum+% tungsten+0.5*(%tantalum+% niobium)+2*(% titanium+% zirconium+% hafnium) is about 0.5%to about 7%.
 12. The implantable medical device of claim 1, wherein thealloy comprises an austenite promoting component comprising manganese,cobalt, platinum, palladium, iridium, aluminum, carbon, nitrogen,silicon, or any combination thereof, wherein % platinum+% palladium+%iridium+0.5*(% manganese+% cobalt)+30*(% carbon+% nitrogen) is greaterthan about 12%, and wherein the alloy comprises a corrosion resistingcomponent comprising chromium, molybdenum, tungsten, tantalum, niobium,titanium, zirconium, hafnium, or any combination thereof, wherein %chromium+% molybdenum+% tungsten+0.5*(% tantalum+% niobium)+2*(%titanium+% zirconium+% hafnium) is about 0.5% to about 7%.
 13. Theimplantable medical device of claim 1, wherein the device is coated witha therapeutic agent.
 14. The implantable medical device of claim 1,wherein the device is coated with a biodegradable hydrogel.
 15. Theimplantable medical device of claim 1, wherein the device comprises ageometry that maximizes the surface to mass ratio.
 16. The implantablemedical device of claim 1, wherein the device comprises a hollow openingor passageway.
 17. The implantable medical device of claim 1, whereinthe biodegradable alloy comprises at least two non-iron metallicelements.
 18. The implantable medical device of claim 1, wherein thebiodegradable alloy comprises manganese and niobium.
 19. The implantablemedical device of claim 1, wherein the biodegradable alloy comprises atleast about 0.01% to about 0.1% non-metallic element.
 20. Theimplantable medical device of claim 1, wherein the biodegradable alloycomprises at least about 0.01% to about 0.1% carbon.